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Review Article
A Brief Review on ProproteinConvertaseSubtilisin/Kexin Type 9
Moumita Ghosh Laskar 1, 2* and Amit Laskar 1, 2
1Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes and 2Molecular Nutrition Unit, Department of Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, C2-94 S-141 86 Stockholm, Sweden Abstract
Proproteinconvertasesubtilisin/ kexin type 9 (PCSK9) is a newly identified secreted protein which plays a vital role in cholesterol homeostasis. PCSK9 increases low-density lipoprotein cholesterol (LDL-C) in plasma by inhibiting its clearance via inducing degradation of low-density lipoprotein receptor (LDLR). In humans, PCSK9 level is modulated by factors such as age, gender, gene mutations, hormones, diet, plant products, fasting and diurnal rhythm. Recent research has proposed inhibition of PCSK9 as a beneficial therapeutic approach to control dyslipidemia, importantly in hypercholesterolemia patients. Thus inhibition of PCSK9 appears to be a considerable promising approach to minimize cardiovascular risk these days. In this review, we acknowledge the recent development in the field of PCSK9. We also highlight the reason behind its choice as a novel therapeutic target to combat LDL-C related imbalances in cardiovascular diseases; an area of focus, increasingly explored by researchers in collaboration with pharmaceutical companies. Key words: Proproteinconvertasesubtilisin/ kexin type 9 (PCSK9), Low density lipoprotein
(LDL), hormones, diet and PCSK9 inhibitor.
*Corresponding author:
Moumita Ghosh Laskar
Metabolism Unit, Department of Endocrinology, Metabolism and Diabetes, Department of Medicine,
Karoli nskaInstitutet at Karolinska University Hospital Huddinge, C2-94.
S-141 86 Stockholm, Sweden
[email protected] Quick Response Code:
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Since then, it has been now well evidenced that PCSK9 plays a vital role in cholesterol metabolism In humans, an increased risk for development of by regulating hepatic LDLR. Though it abundantly atherosclerosis and cardiovascular events is expresses in liver, but it is also present to a lesser extent in the small intestine, kidney, and central cholesterol metabolismCholesterol is a molecule nervous system. In human, PCSK9 gene is present of fundamental importance for normal cell on chromosome 1p32.3. PCSK9 strongly correlates function, and serves as a precursor for steroid hormones and bile acids. The liver has a crucial dyslipidemia and atherosclerosis. Structurally, role in cholesterol homeostasis. In the liver, alone with a 30 amino acid signal sequence, cholesterol is converted to bile acids that are PCSK9 contains a prodomain (amino acid 31-152), secreted into bile together with free cholestero a catalytic domain (amino acids 153-425) and a cysteine histidine rich C-terminal domain (amino cholesterol. Cells also acquire cholesterol by de acids 426-692)Over expression or gain of novo synthesis. In blood, plasma cholesterol is function (GOF) mutation of PCSK9 gene leads to transported within lipoproteins such as high-density hypercholesterolemia whereas, loss of function (LOF) mutations of PCSK9 gene lead to lipoproteins (LDL), very low-density lipoproteins hypocholesterolemia and reduced cardiac risk. (VLDL) and chylomicrons. Various surface receptors such as low-density lipoprotein receptor PCSK9 and its role on LDLR
(LDLR), scavenger receptor class B type1 (SRB-1) and very-low-density (VLDLR) are involved in the cellular uptake of proproteinconvertase family, is a secreted protein which presumably is secreted from the liver. Within hepatic cells, PCSK9 is synthesized as a precursor (72 Kda) which undergoes autocatalytic especially LDL-cholesterol (LDL-C) are linked to cleavage and produces 2 products, the prosegment cardiovascular diseIn human blood, 70% of and the mature PCSK9 (63 KDa). This the cholesterol is within LDL particlesMost autocatalytic cleavage is required for maturation of plasma LDL is taken up by liver while the rest is PCSK9 and also for its trafficking from ER to distributed to peripheral tissues and to the adrenals and gonadsModulation of hepatic LDL circulationBefore secretion, mature PCSK9 receptors (LDLRs) plays a vital role for LDL-C post-translational level in plasma by influencing the clearance of modifications such as N-glycosylation, sulphation LDL-C from circulation. LDLR numbers are and phosphorylation. On the cellular membrane, the catalytic domain of circulating PCSK9 binds to transcriptional (via the sterol regulatory element- the epidermal growth factor precursor homology binding protein (SREBP) -2 pathway) and b) domain-A (EGF-A) of the LDLR in a calcium- post-transcriptional dependent manner.Then the complex of LDLR/PCSK9 is internalized within the cell via (PCSK9) mechanismsThe very important clathrin-mediated endocytosis thus entering the role of post-transcriptional regulation by PCSK9 endosomal pathwayThe bonding affinity of was established during last decade. PCSK9 induces LDLR/PCSK9 complex is increased in the low pH the degradation of hepatic LDLR, thereby elevating of endosomAs a result of changes in the cholesterol levels in plasma. Higher PCSK9 levels conformation of LDLR its recycle back to cell correlate with cardiovascular complications and thus, inhibiting PCSK9 could be beneficial for LDLR/PCSK9 is then directed to the lysosome and minimizing cardiovascular risks in human. destined for lysosomal degradation. Plasma levels of PCSK9 generally correlate positively with the plasma LDL-C. PCSK9 induces lysosomal LDLR degradation after binding to the LDLR Previously known as neural apoptosis-regulated (Figure 1). As a result, it down-regulates cellular convertase 1, PCSK9 was discovered in 2003.
LDLR numbers thereby diminishing the cellular IJEPP 2015, 1 (1), 29-36
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uptake of LDL particles and increasing plasma regulated during menstruation cycle depending on the estrogen levels in fertile femHowever, a intracellular PCSK9 could also lead the lysosomal study in Chinese population suggests otherwise, degradation of LDLR. Within the hepatocyte, where no such correlation was found before LDLR transport toward to the cellular membrane, the prosegment PCSK9 binds to LDLR Testosterone, a male sex hormone reduces hepatic and forms the prosegment PCSK9 /LDLR complex PCSK9 mRNA and protein and also circulating which is then directed from Golgi to the lysosome PCSK9 in pig whereas a study in human has for degradation However, the underlying shown that circulating PCSK9 is not related to testosterone in males. degradation of LDLR is not fully understood. Thyroid hormones such as tri-iodo-thyronine (T3) PCSK9 relation to age, gender and other
and thyroxine (T4) are synthesized in the thyroid metabolic factors
gland. These hormones are proven to be the major regulators It is known that plasma cholesterol, especially the Hypothyroidism is strongly associated with levels of LDL-C increases in human with age. In enhanced levels of plasma total and LDL females, this increase of LDL-C is much prominent cholesterol whereas in hyperthyroidism, it is vice after menopause. Studies have shown that PCSK9 versa. Results indicate that PCSK9 level is lower in levels also increase with age in a healthy patients with hyperthyroidism. Treatment with population, and it is higher in females then in eprotirome, a thyroid hormone supplement reduces males.It is also proposed that PCSK9 is one of the reasons for age-related induction of LDL-C at least in females. In addition, PCSK9 has Glucagon and Insulin, two important hormones been shown to be positively correlated with LDL- involved in carbohydrate homeostasis, have also C, total-C, triglyceride, insulin, body mass index shown to be correlated with PCSK9.Glucagon (BMI), and glucose and with cholesterol synthesis is a peptide hormone produce from alpha cells of the pancreas, increases concentration of glucose in blood whereas insulin, another peptide hormone Hormonal effects on PCSK9
produced from beta cells of the pancreas regulates carbohydrate metabolism and enhances glucose Studies have shown that LDL-C metabolism is absorption from blood to musStudies have modulated by hormones such as estrogen (E2), shown that these two hormones may influence Testosterone (T), adrenocorticotropic hormone PCSK9 in human.
(ACTH), thyroid hormone (TH), Growth hormone (GH) and glucagon in human and in animals.
Dietary effects on PCSK9
Studies have also shown that hormones such as estrogen, testosterone, thyroid hormone and Dietary nutrition has also shown to regulate PCSK9 in animals and humans. Several studies have found transcriptionally post-transcriptionally the sterols influences PCSK9 mRNA expressions animals, as well as in human. via SREBP2 pathway. Mediterranean diet and diet containing vegetable polyunsaturated fatty Estrogen, a female sex hormone has shown to acids (PUFAs) reduce circulating PCSK9 in reduce hepatic PCSK9 mRNA and protein levels in human. In humans, it has been also described animFurthermore, in humans, supra- that high fructose containing diet induces an physiological levels of estrogen (prior to in vitro increase in plasma PCSK9 concentration.
fertilization) reduce plasma PCSK9 and LDL PCSK9 is also affected by fasting and follows a cholesterol levelsHowever, from post-hoc diurnal rhythm.Additionally, Berberine, an analysis of postmenopausal females, taking isoquinoline plant alkaloid, found in plants such as estrogen supplement indicates that exogenous Berberis vulgaris, Coptis chinensis, Berberis estrogen therapy has failed to reduce circulating aristata inhibit hepatic and circulating PCSK9 PCSK9 in postmenopausal womenIt has been thereby reducing cardiovascular risk. reported that PCSK9 and LDL-C may also be PCSK9 as a therapeutic target

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Figure 1: A) Degradation of LDLR and involvement of PCSK9; B) LDL-C clearance and recycling of
Proproteinconvertasesubtilisin/kexin type 9- (PCSK9). Table 1: Pharmaceutical advancement in development of PCSK9 inhibitors
Treatment approaches to
Pharmaceutical companies
Present status and
inhibit PCSK9
Monoclonal antibodies
Sanofi/Regeneron FDA approved, July 2015 FDA approved, August 2015 Phase III ongoing Phase II completed Phase I completed Alnylam Pharmaceuticals Phase I completed Phase I recruiting Mimetic peptides
Phase I completed Small molecules
Shifa Biomedical Corp Preclinical completed Abbreviations: Proproteinconvertasesubtilisin/kexin type 9- (PCSK9); Food and drug administration (FDA).
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